Methods and systems for neural maintenance and regeneration

ABSTRACT

Methods and systems are described that release one or both of a neurotrophin and an inhibitor of the degradation of the neurotrophin within or in the vicinity of a highly innervated tissue. In some embodiments, the method includes regulating the release of the neurotrophin and the inhibitor of degradation over time. In some embodiments, the method includes monitoring the concentration of the neurotrophin over time. The system may include a device or multiple devices for the release of the neurotrophin and the inhibitor as well as a controller. In some embodiments the system may include a sensor device and/or an imaging device capable of detecting the concentration of the neurotrophin over time. The release of the neurotrophin and inhibitor of degradation may be part of a controlled release system and regulated over time.

This application is a divisional of co-pending U.S. application Ser. No.11/150,861, titled METHODS FOR ELEVATING NEUROTROPHIC AGENTS filed onJun. 10, 2005.

TECHNICAL FIELD

The present application relates, in general, to methods and systems formodulating the concentration of neurotrophins within or in the vicinityof neural tissues.

SUMMARY

Exemplary methods and systems are described for modulating theconcentration of one or more neurotrophins within or in the vicinity ofneural tissues. In one aspect, a method includes elevating theconcentration of at least one neurotrophin within a neural tissue of amammal and elevating the concentration of at least one inhibitor ofdegradation of the neurotrophin within the neural tissue. In someaspects, the method includes regulating the concentration of theneurotrophin over time and/or monitoring the concentration of theneurotrophin over time.

In one aspect, a system includes a neurotrophin release device capableof releasing a neurotrophin within or in the vicinity of a neuraltissue. In another aspect, the system includes an inhibitor releasedevice capable of releasing an inhibitor of degradation of theneurotrophin. The system may include one or more sensors capable ofsensing the concentration of a neurotrophin and/or an inhibitor and acontroller for controlling the release of neurotrophin and/or inhibitorof neurotrophin degradation. Certain embodiments may include thecapability of transmitting data to a remote device for display andevaluation, and/or for receiving control signals from a remote device.

The foregoing is a summary and thus contains, by necessity,simplifications, generalizations and omissions of detail; consequently,those skilled in the art will appreciate that the summary isillustrative only and is not intended to be in any way limiting. Variousadditional aspects of the inventive method and system are set forth anddescribed in the claims, drawings, and text forming a part of thepresent application. Other aspects and advantages of the methods andsystems described herein as defined solely by the claims, will becomeapparent in the detailed description set forth herein.

BRIEF DESCRIPTION OF THE FIGURES

The use of the same symbols in different drawings typically indicatessimilar or identical items.

FIG. 1A illustrates a mechanism of degradation of a neurotrophin;

FIG. 1B illustrates an inhibition of the neurotrophin degradationmechanism that is illustrated in FIG. 1A;

FIG. 2 illustrates an embodiment of a system for modulating levels of aneurotrophin;

FIG. 3 illustrates an embodiment of a system including a remote device;

FIG. 4 illustrates another embodiment of a system including a remotedevice and a single release device; and

FIG. 5 illustrates an embodiment of a system for implantation within theeye of a subject

DETAILED DESCRIPTION

Methods and systems as described and illustrated herein are thought tobe particularly beneficial with regard to preservation, restoration orenhancement of sensory function, but they are not limited to theseapplications. Sensory tissues that may be beneficially treated include,but are not limited to, auditory, olfactory, visual, and somatosensorystructures such as the cochlea, olfactory bulb, and retina. In addition,structures of both the central and peripheral nervous systems may betreated with regard to preservation, restoration or enhancement by themethods and systems described herein. In some embodiments, the methodsand systems described herein may find application in the treatment ofneurons damaged though injury, including injuries sustained duringsurgery. In some embodiments, the methods and systems described hereinmay find application in conjunction with neural tissue grafts, implantsor related surgical therapies. In some embodiments, the methods andsystems described herein may find application in testing patientresponse to neurotrophins for diagnostic and/or therapeutic purposes. Insome embodiments the methods and systems described herein may findapplication in monitoring patient status over time and/or acting inconjunction with other therapies. While the concentration(s) ofneurotrophin(s) may be modulated in a wide variety of organisms, it iscontemplated that methods and systems as described and illustratedherein will find greatest application in humans and selected non-humanmammals. Some embodiments for instance, may find application in adomesticated mammal such as a dog, cat, horse, cow, sheep or goat.

As used herein, the term “neurotrophin” refers to any biochemical agentthat results in an increase in neuronal metabolic activity, mitoticactivity, growth, differentiation or survival when it is introduced intoor in the vicinity of a neuron. The effects on a neuron generated by aneurotrophin are “neurotrophic” effects. Neurotrophins may includeeither or both endogenous substances which are naturally present in sometissue at some stage of life and non-endogenous substances which exhibitneurotrophic effects. A neurotrophin may be any molecule or biologicalcomplex which has neurotrophic effects and may, for example, includepeptides, proteins, protein complexes, cyclic nucleoside monophosphatesor hormones. Neurotrophin also refers to both what is commonly referredto as the neurotrophin protein family (e.g. nerve growth factor (NGF),neurotrophin-3 (NT-3)etc.) as well as other factors with neurotrophiceffects. Exemplary neurotrophins include NGF, brain derived neurotrophicfactor (BDNF), NT-3, neurotrophin 4 (NT-4), adenosine 3′,5′-cyclicmonophosphate (cAMP), and the like, and derivatives or analogues thereofand in any combination thereof. See e.g. Hefti, Ann. Rev. Pharmacol.Toxicol., 37: 239-267, 1997, Cai et al., J Neurosci., 21(13):4731-4739(2001). For example, cAMP derivatives and analogs include forskolin,dibutyric-cAMP (db-cAMP), adenosine 3′,5′-cyclic monophosphate benzylester (8-AMP-Bn), 8-chloroadenosine-3′,5′-cyclic monophosphate(8-Cl-cAMP), and the like, or any agent that influences cAMP mediatedmetabolic pathways. See e.g. Rydel et al., PNAS 85, 1257-1261, 1988. Insome situations, the neurotrophin may be a metabolic precursor of thebiochemically active agent, in which case the neurotrophin precursor issusceptible to being altered by one or more endogenous metabolic factorsto generate an active form of the neurotrophin. In some situations, morethan one neurotrophin precursor molecule of the same or different typemay combine or complex to form an active neurotrophin. A neurotrophinmay be made up of several subunits or component parts which may be thesame or different proteins, saccharides or other molecules. As anon-limiting example biochemically functional NGF consists of a proteindimer (see e.g. Sofroniew et al., Annu. Rev. Neurosci. 24:1217-1281,2001).

By way of background and not wishing to be bound by theory,neurotrophins have been shown to have many influences on cells atdifferent times in the life cycle of an organism, including regulationof neural development, plasticity, function, maintenance and survival.See e.g. Huang and Reichardt, Annu. Rev. Neurosci 24:677-736, 2001;Petruska and Mendell, Neurosci. Lett. 361:168-171, 2004 and D'Sa et al.Bipolar Dis. 4:183-194, 2002. Multiple cells normally releaseneurotrophins during development and through the life cycle of anorganism, including after injury. See e.g. Huang and Reichardt, Annu.Rev. Neurosci 24:677-736, 2001; Hochhaus et al., BMC Pediatrics 1:2,2001; Spencer and Filbin, J. Anat. 204:49-55, 2004. Biochemically activeneurotrophins may come from either endogenous or exogenous sources. Forexample, endogenous neurotrophins are produced by skin, vascular andsmooth muscle cells, endocrine tissues and salivary glands during thenormal life cycle of these cell types (reviewed in Sofroniew et al.,Annu. Rev. Neurosci. 24:1217-1281, 2001). Exogenous neurotrophins havealso been shown to have neuroprotective effects when supplied to theischemic hippocampus (see e.g. Wu and Pardridge PNAS 96:254-259, 1999).Some antidepressants used in treating chronic depression haveneurotrophic effects in the hippocampus (see e.g. Castren Curr. Opin.Pharma., 4:58-64, 2004 and D'Sa et al., Bipolar Dis. 4:183-194, 2002).

Both endogenous and exogenous neurotrophins typically do not persistindefinitely within the body of an organism, but are degraded byneurotrophin degrading agents. As used herein, the term “neurotrophindegrading agent” refers to any factor that directly or indirectly causesa chemical, structural, or functional alteration to a neurotrophin,which results in a reduction in the neurotrophin's basal neurotrophicactivity. This chemical, structural, or functional alteration may bepermanent or it may be transitory. A neurotrophin degrading agent is anymolecule or biological complex which has neurotrophin degrading effectsand may, by way of non-limiting examples, include peptides, proteins,protein complexes, enzymes, antibodies or hormones. Substances whichfunction as neurotrophin degrading agents can be naturally presentwithin living organisms, and influence the concentration ofneurotrophins within cells or tissues of the organisms. In someembodiments, the neurotrophin degrading agent is an enzyme. In addition,there exist “inhibitors of neurotrophin degradation”, which can be anyfactor that cause directly or indirectly chemical, structural, orfunctional alteration(s) to a neurotrophin degrading agent resulting ina reduction in its basal activity. This chemical, structural, orfunctional alteration may be permanent or it may be transitory. Theinhibitor of degradation may be a peptide, a protein, an antibody, achemical or other factor or combination thereof that reduces theactivity of a neurotrophin degrading agent. In one exemplary embodiment,the neurotrophin may be cAMP, the neurotrophin degrading agent may be aphosphodiesterase, such as PDE4, and the inhibitor of degradation may be4-[3-(Cyclopentyloxy)-4-methoxy-phenyl]-2-pyrrolidinone (rolipram) (seee.g., Perry and Higgs, Curr. Opin. Chem. Bio. 2: 472-481, 1998).

As used herein, the term “neural tissue” refers to both central andperipheral nervous system components, and to tissues and structureswithin the body which include or are associated with one or moreneuronal components, but are not necessarily themselves neuronal or ofneural origin. These include “highly innervated tissues”, which aretissues that contain, are supplied by, or are innervated by largenumbers of nerve cells or processes either efferent or afferent.Examples of highly innervated tissues include the cochlea, the olfactorybulb and the retina. Highly innervated tissues are not limited to thespecific examples listed herein and include tissues that contain a largenumber of somatosensory fibers such as portions of the skin, bones,muscle, or joint capsules, or tissues or organs that are under directneural regulation such as certain glandular tissues and portions of thedigestive system. In some cases, the concentration of neurotrophin maybe elevated within a sensory organ, which is any tissue that detectsstimuli from the environment. Examples of sensory organs include theeye, ear, nose and tongue. The concentration of neurotrophin may beelevated in the entire sensory organ and/or within a “therapeuticallyeffective region” of it. As used herein, the term “therapeuticallyeffective region” refers to a region which allows for transfer of theintroduced agent by active or passive means to the cells of interest inthe particular situation. In some situations, the therapeuticallyeffective region is within or immediately adjacent to a highlyinnervated tissue while in others it may be at some distance within thebody (see e.g., Montcouquiol and Corwin, J. Neurosci., 21(31:974-982,2001: Castren Mol. Neurobio., 29:289-301, 2004).

As used herein the term “neural support tissue” refers to tissues andcells which give at least one neuron physical, physiological ormetabolic support. Examples of neural support tissues include glialcells such as oligodendrocytes. Schwann cells and astrocytes, andvascular structures in the region of a neuron. In many situations,neural support tissue is located in the region or vicinity of a neuron,but in some cases it may be located in another region of the body andsupport the neuron metabolically or physiologically by directlyproducing or indirectly causing the production of neural supportsubstances. In some situations a neural support tissue produces at leastone “neural support substance”, which is a substance that acts tosupport the neuron metabolically or physiologically and acts eitherregionally or at a distance within the body. Examples of neural supportsubstances include neurotrophins, neuron apoptosis inhibitors,suppressors of inflammatory responses that may damage neurons,suppressors of autoimmune factors that may damage neurons and neuronalsurvival promoters such as anti-beta (β) amyloid antibodies.

Pathway A of FIG. 1 illustrates an exemplary mechanism for degradationof a neurotrophin 10 by a degrading agent 30. Pathway A depicts aphysiological process whereby the neurotrophin 10 binds to the degradingagent 30 to produce neurotrophin degradation products 20, which may beinactive or degraded neurotrophin. Depending on the particularneurotrophin and degrading agent, they may bind irreversibly and bedegraded together or only the neurotrophin may be degraded and thedegrading agent may be released intact. The degrading agent may alsoretain some portion of the original neurotrophin molecule after anotherportion is released. More than one unit of the degrading agent may alsobind to more than one unit of the neurotrophin. A unit of theneurotrophin and/or the degrading agent may be a complex of multiplemolecules or a single molecule, depending on the embodiment.

As depicted in pathway B of FIG. 1, when an inhibitor of degradation 40is present, neurotrophin degrading agent 30 may bind to inhibitor ofdegradation 40, resulting in a reduction in neurotrophin degradingactivity. Although a single-molecule inhibitor of degradation isdepicted diagrammatically in FIG. 1, the inhibitor may be comprised of asingle molecule, multiple molecules or a chemical compound which in theaggregate results in an inhibition of the degradation of theneurotrophin. In some embodiments, the neurotrophin degrading agent isirreversibly bound to the inhibitor while in others the binding istransient. The inhibitor may chemically or structurally alter thedegrading agent so that its degrading activity is reduced, or it mayrelease the degrading agent unaltered after some time period or inresponse to a chemical reaction. The inhibitor may bind to the samemolecular site on the degrading agent as the neurotrophin or it may bindto a different molecular site. The inhibitor of degradation may alsobind directly to the neurotrophin.

One skilled in the art will appreciate that both pathways A and B (shownin FIG. 1) may operate simultaneously in the same cell or tissue. Inthis situation, by elevating the relative concentrations of neurotrophinand inhibitor of neurotrophin degradation, the relative activity of thetwo pathways and/or the total concentration of neurotrophin may bemodulated. A person skilled in the art will appreciate that the presenceof an inhibitor of degradation of the neurotrophin will not result inblocking the degradation of all neurotrophin molecules, and that eventsdepicted in pathway A and events depicted in pathway B of FIG. 1 mayboth occur, although at different relative rates, in any givenembodiment. The rates of either degradation of the neurotrophin orinhibition of degradation are dependent on several factors, includingbut not limited to the relative concentrations of the neurotrophin, thedegrading agent and the inhibitor of degradation as well as the kineticactivity of each. As used herein, the term “concentration” refers to themolar quantity of a molecule or compound and/or its biochemical analogsin a region which may be a cell, a subcellular region, a tissue or alocation in the vicinity of one of these. The “level” of a neurotrophinand/or an inhibitor of degradation of a neurotrophin is theconcentration within a localized region such as within a sensory organ,a highly innervated tissue or other relevant region. As will beunderstood by one skilled in the art, the concentrations ofneurotrophin, inhibitor of degradation of the neurotrophin and degradingagent are likely to be interdependent in any given embodiment and varyover time. Therefore while it is possible to modulate and/or control thelevels of neurotrophin and/or inhibitor of degradation of neurotrophinto some degree, the concentration of both of these substances will beinherently dynamic in any given situation.

In various embodiments, neurotrophins and inhibitors of neurotrophindegradation may be introduced into therapeutically effective region(s).While elevating the levels of neurotrophin may ultimately affect aspecific cell or group of cells, it is not required that theneurotrophin be delivered into the cell or cells to be affected, nor isit necessary that the concentration of neurotrophin within the cell orcells be measured directly. As will be understood by one skilled in theart, the elevation of the concentration of one or more neurotrophinsand/or one or more inhibitors of degradation of a neurotrophin and/orone or more neural support substances in the vicinity of a neural tissueor highly innervated tissue within the body of a mammal may result inthe elevation of the concentration of neurotrophin within the tissue orcells within the tissue. In some embodiments, therefore, a “point ofrelease” or multiple points of release either within or in the vicinityof the tissue may be effective to modulate the concentration ofneurotrophin as desired. As used herein, a “point of release” is thelocation where the substance is primarily released into the body. Insome embodiments, the point of release is where the substance isphysically released into the body, while in others the point of releaseis where the substance is metabolized into its biochemically activeform. Introduced neurotrophins may be identical to endogenously producedneurotrophins, or may be analogs of endogenous neurotrophins, and may bestructurally similar, functionally similar, or both. Moreover,substances that may be introduced include substances that are precursorsor components of neurotrophins which, upon delivery into a neuraltissue, are altered by endogenous factors to produce a neurotrophin,such that an increase in the concentration of the released substance inthe tissue produces a corresponding increase in concentration of theneurotrophin. In some embodiments, the substance or substances will bereleased once while in others they will be released on multipleoccasions. In some embodiments, more than one neurotrophin and/or morethan one inhibitor of degradation and/or more than one neural supportsubstance will be released in order to attain the desired effects. Morethan one release strategy may be effective or desired in any givensituation. Methods and systems as illustrated herein may operate tomodulate neurotrophin concentrations to or toward normal levels (i.e.,in subjects having initially lower than normal neurotrophin level(s), orto modulate neurotrophin levels beyond physiological concentrationlevels.

The simplified exemplary system of FIG. 2 includes an implantableneurotrophin release device 60 capable of releasing a neurotrophin andan implantable inhibitor release device 70 capable of releasing aninhibitor of degradation of the neurotrophin. In many embodiments, therelease devices may be implantable and present in the body for anextended time period such as days, weeks, months or years while in otherembodiments the release devices are only present for a short time duringtreatment. Release devices 60 and 70 may be two separate devices, asillustrated in FIG. 2, or may be configured as a single device. In someembodiments there may be a plurality of release devices. Release devices60 and 70 may be controlled release devices that include means toregulate the release of neurotrophin and/or at least one inhibitor ofdegradation, respectively, over time, in response to a control signalgenerated by controller 80. Controller 80 may be an electroniccontroller and may include a signal generator and/or a microprocessor.Controller 80 may be connected to the neurotrophin release device 60 andinhibitor release device 70 by any means known in the art, includingelectronic cabling, wireless or other connections. Controller 80 maygenerate at least one control signal that is transmitted to at least oneof the neurotrophin release device and/or the inhibitor release devicevia said connection. Controller 80 may also be implantable or partiallyimplantable in some applications.

In the simplified exemplary embodiment depicted in FIG. 2, controller 80receives signals 51, 91 from neurotrophin sensor 50 and inhibitor sensor90. The neurotrophin sensor 50 is capable of detecting a concentrationof the neurotrophin, while inhibitor sensor 90 is capable of detecting aconcentration of the inhibitor of neurotrophin degradation. Although 2sensors are depicted in FIG. 2, in some embodiments there may be onlyone sensor or more than 2 sensors. In addition, multiple sensors may beintegrated into a single device. Depending on the embodiment, thesensors may detect and quantify the concentrations of the relevantsubstance(s) and/or they may detect concentrations only at a particularlevel or range. In some embodiments the sensors detect inducedactivities from the release, such as a resulting biochemical reaction.The data from the sensors may be used to monitor the concentration ofneurotrophin within the highly innervated tissue. Based upon the valuesof signals 51 and 91 from neurotrophin sensor 50 and inhibitor sensor90, respectively, controller 80 determines a suitable modification tothe release of neurotrophin and inhibitor of neurotrophin degradation inorder to appropriately control the level of neurotrophin. Controller 80then produces neurotrophin release device control signal 61, which issent to neurotrophin release device 60 and inhibitor release devicecontrol signal 71, which is sent to inhibitor release device 70, toproduce the desired modification to the activity of these devices.

FIG. 3 depicts another exemplary embodiment of the system that includesneurotrophin release device 60, inhibitor release device 70, andcontroller 80. In this exemplary embodiment, a single neurotrophinsensor 50 provides a signal 51 to controller 80. In some embodiments theaddition of more neurotrophin, the addition of an inhibitor ofdegradation of the neurotrophin or both may be regulated based on thesensor data. Operation of detectors 50 and release devices 60 and 70 aresubstantially as described in connecting with FIG. 2. Also included isremote device 100, which may provide remote monitoring and/or controlcapabilities beyond those provided by controller 80. The remote devicemay be coupled to the sensor(s), the release device(s) and/or thecontroller. In some embodiments, the remote device 100 and thecontroller 80 may be combined into one device. Remote device 100 may beconfigured to allow a user to monitor the effects of the implantedsystem, to control the operation of the system, or both. The user may bethe subject within whom the system sensor 50, release devices 60 and 70,and controller 80 are implanted, or another user such as a physician orother medical personnel.

The concentration of neurotrophin may also be graphically displayedthrough an imaging device or devices coupled to the controller. Animaging device may be a remote device 100 as depicted in FIG. 3. In someembodiments, an imaging device may be used to monitor the concentrationof neurotrophin over time. An imaging device may be capable of imagingthe levels of the neurotrophin or neurotrophin-induced biochemicalactivity within a therapeutically effective region of the sensory organ.Depending on the embodiment, the therapeutically effective region maycomprise the cochlea, the olfactory bulb or the retina, or pertinentfractions thereof. The imaging device may be adapted to receiveinformation from one or more sensors and capable of displayinginformation from at least one sensor. For example, remote device 100 mayinclude an imaging device, a display device and/or an input device. Adisplay device may be, for example, a computer monitor or various otherdisplay devices as are known in the art. In one aspect, remote device100 may function as an imaging device and a display device that iscapable of generating a graphical depiction of the neurotrophinconcentration detected by the sensor device 50 as a function of time.Alternatively or in addition, remote device 100 may provide a numericaldisplay specifying the detected concentration at the current time, or atsome other time. A display device may be configured to display multipleparameters of interest simultaneously or a single parameter. Displayedparameters may include, for example, the detected concentration ofneurotrophin, and/or the release rates of neurotrophin and inhibitor ofneurotrophin degradation provided by release devices 60 and 70. Variousdisplay formats may be used as are known to those of skill in the art.Other displayed parameters may include various parameters relating tothe control scheme used to regulate rates of release of substances fromrelease devices 60 and 70.

The remote device may be user configurable to display user-selectedparameters in a user-selected format. The remote device may beconfigured to display menus on a display device and to receive userinput indicating the user's selection of menu options from an inputdevice. An input device may include a keyboard, an instrument controlpanel, a microphone (in which case voice commands may be processed byvoice recognition hardware or software), or by various other input meanswell known to those of skill in the art. In some embodiments, there maybe multiple remote devices located at the same or multiple location,said remote devices of the same or different types. In some embodiments,display devices and input devices may be formed integrally as atouch-screen so that a single device may provide both display and inputfunctions. In addition to selecting and controlling the display of dataon a display device, the entry of commands at an input device may beused to change the configuration or programming of the controller. Forexample, in some embodiments the user may change the type of controlscheme used to regulate rates of release of substances from the releasedevice or devices such as by changing the target value from a constantstored value to a calculated value or by changing stored constants usedin the control scheme.

It is contemplated that remote device 100 is located externally to thebody of the subject in which sensors 50, 90 and release devices 60, 70are implanted. As described in connection with the embodiment of FIG. 2,controller 80 may be implanted within the body of the subject, either inthe vicinity of sensor 50 and release devices 60 and 70, or at someother location within the body, or may be external to the body. Ifcontroller 80 is external to the body, controller 80 and remote device100 may be constructed as a single device. Remote device 100 may beconnected to controller 80 by any means known in the art, including anelectronic cable or a wireless connection. If remote device 100 isconnected via an electronic cable, the connection may be made via atransdermal connector, as is known in the art. Such a connection methodmay be suitable for occasional uses of the system in combination withremote device 100 such as for intermittent medical monitoring or forexperimental use. If continuous use of the system in combination withremote device 100 is desired, it may be preferable to connect remotedevice 100 with controller 80 via a wireless connection, such as viaradio frequency, infrared or other wireless connections.

FIG. 4 illustrates another embodiment of a system for modulating theconcentration of a neurotrophin. In this exemplary embodiment of thesystem, a single release device 110 is used. Release device 110 may becapable of releasing a neurotrophin, an inhibitor of degradation of theneurotrophin, or a composition containing a mixture of neurotrophin andan inhibitor of neurotrophin degradation. Release device 110 and sensors50 and 90, which are capable of detecting the concentrations ofneurotrophin and inhibitor of neurotrophin degradation, respectively,are linked to controller 80. This exemplary system also includes animaging device 100. Sensors 50 and 90, release device 110, and remotedevice 100 may be connected to the electronic controller 80 by variousmethods as described previously. FIG. 4 serves to provide furtherillustration that the various system components, including sensors,release devices and the remote device, may be combined in various ways.Possible combinations are not limited to the examples presented herein,and systems that use various combinations of system components invarious configurations may be appropriate based on a particularembodiment.

FIG. 5 illustrates in detail a specific exemplary embodiment, whichincludes implanted structures for delivery of neurotrophin to the eye.Such a system may have application, for example, in the restoration ofvision damaged by neural degeneration at the retina such as the types ofdegeneration seen in aging as well as in diseases such as retinitispigmentosa and various forms of macular degeneration (see e.g. Adler etal., Mol. Vis. 5:31-36, 2004). Some potential exemplary applications foran embodiment like that diagrammed in FIG. 5 include the treatment ofdiseases of the optic nerve such as glaucoma, optic neuritis andischemic optic neuropathy (e.g. Margalit and Sadda, Art. Organs,27(11):963-974, 2003). Other potential exemplary applications includethe treatment of diseases of the retina, such as various types ofmacular degeneration and diabetic retinopathy (e.g. Green, Mol. Vis.5:27-36, 1999: Ciulla et al., Diabetes Care 26(9):2653-2664, 2003).Visual inputs enter eye 130 through cornea 140 and are focused on retina150 by lens 160. Photodetectors located in the retina may be activatedby a visual input to generate neural activity that is carried to thebrain via optic nerve 170. Release device 110 releases a neurotrophin inthe vicinity of retina 150, while sensor 50 detects the concentration ofneurotrophin in the vicinity of the retina 150. Controller 100 islocated external to eye 130 and communicates with sensor 50 and releasedevice 110 via wireless connections in this embodiment. Sensor 50 andrelease device 110 may be placed on the retina at optic disc 180, theregion where the optic nerve enters the eye. Since no photoreceptors arefound at the optic disc, placement of structures at this location shouldnot interfere with vision.

Neurotrophin and/or neurotrophin degradation inhibitor release devices60, 70, and 110, as illustrated in the exemplary illustrations of FIGS.2 through 5, may be any of various types of release devices capable ofreleasing substances in a controlled fashion responsive to a controlsignal. The neural support substances may be released in combinationwith one or more neurotrophins, one or more inhibitors of degradation ofa neurotrophin, or both. In some embodiments, suitable devices mayinclude, for example, polymeric components which, when subjected to anapplied control such as e.g., electric, magnetic field, change intemperature, change in pH, etc. change in configuration to release adrug or other substance contained by or within the polymer (“Polymers inControlled Drug Delivery”, Brannon-Peppas, Medical Plastics andBiomaterials, November 1997. p. 34). Polymers carriers may be fashionedin a variety of forms, including for example, pellets, discs or capsules(see e.g., Goodell et al., Am. J. Hosp. Pharm. 43:1454-1461, 1986:Langer et al., “Controlled release of macromolecules from polymers”, inBiomedical polymers. Polymeric materials and pharmaceuticals forbiomedical use. Goldberg, E. P., Nakagim, A. (eds). Academic Press. pp.113-137, 1980; Rhine et al., J. Pharm. Sci. 69:265-270, 1980; Brown etal. J. Pharm Sci. 72:1181-1185, 1983 and Bawa et al., J. ControlledRelease 1:259-267, 1985). Neurotrophins and inhibitors of neurotrophindegradation, and compositions thereof may be linked by occlusion in thematrices of a polymer, bound by covalent linkage, or encapsulated inmicrocapsules. Within certain embodiments, neurotrophic compositions areprovided in non-capsular formulations, such as microspheres (rangingfrom nanometers to micrometers in size), pastes, films or sprays.Preferably, neurotrophic compositions of the present invention isfashioned in a manner appropriate to the intended use. Within certainaspects of the present invention, the composition should bebiocompatible, and release one or more neurotrophin(s) and inhibitor(s)of neurotrophin degradation over a period of several seconds, minutes,hours, days, or months. For example, “quick release” or “burst”compositions are provided that release up to 50% (w/v) of neurotrophinsand inhibitors of neurotrophin degradation over a desired period. Such“quick release” compositions should, within certain embodiments, becapable of releasing chemotherapeutic levels (where applicable) of adesired neurotrophin and inhibitor of neurotrophin degradation. In otherembodiments, “low release” neurotrophic compositions are provided thatrelease less than 1% (w/v) of a neurotrophin and inhibitor ofneurotrophin degradation over a desired period. In certain aspects,neurotrophin and inhibitor of neurotrophin degradation compositions ofthe present invention should be stable for several months and capable ofbeing produced and maintained under sterile conditions.

Other suitable release devices may include a reservoir of the substanceto be released in combination with a controllable pump mechanism formoving the substance out of the reservoir. Such devices are described,for example, in U.S. Pat. Nos. 5,476,446, 5,676,655, 5,713,847,6,045,528, 6,304,787, 6,309,410, 6,440,102 and 6,726,678, all of whichare incorporated herein by reference in their entirety. A number ofdesigns for microscale (often MEMS-type drug delivery devices) are alsoknown. Examples of such devices are described in U.S. Pat. Nos.5,797,898, 6,408,878, 6,432,050, 6,454,759, 6,537,256, 6,551,838,6,668,190, 6,669,683 and 6,673,596, all of which are incorporated hereinbe reference in their entirety. A good review of methods and system forin vivo drug delivery is provided by “Small-scale systems for in vivodrug delivery”, LaVan et al., Nature Biotechnology, Vol. 21, No. 10,October 2003. In some embodiments, the release device is of a type thatis not implantable. Examples of such devices may be found in U.S. Pat.Nos. 6,075,066, 6,586,023, 6,756,053, 6,723,077 and 6,684,879, which areincorporated herein by reference. While the above described drugdelivery devices are exemplary of devices that may be suitable for useas release devices; the practice of these methods and approaches is notlimited to these specific devices. It will be appreciated that dependingupon factors such as, but not limited to, the intended target for thereleased substances, the particular substances to be released, and theintended duration of treatment, that certain delivery devices will bemore or less appropriate than others, and that selection of a suitabledevice may be made by a practitioner of skill in the art, based upon theguidance provided herein. In some embodiments, a plurality of releasedevices of the same or different types may be used.

Substances released from the release device or devices may include anysubstances that act to modulate neurotrophin activity in the region nearthe release device. Such substances include neurotrophins and inhibitorsof neurotrophin degradation, and precursors and combinations thereof.

The approaches described herein provide methods for altering levels ofneurotrophin (e.g., to enhance nerve growth) by administering aneffective amount of neurotrophins and inhibitors of neurotrophindegradation. The neurotrophins and inhibitors of neurotrophindegradation are preferably part of a composition when used in themethods herein. Generally, the compositions comprise one or morecompounds of the invention and an appropriate carrier, excipient ordiluent, and may range from being suitable or acceptable forenvironmental uses, to being suitable or acceptable for veterinary uses,to being suitable or acceptable for human use (i.e., pharmaceuticallyacceptable). Pharmaceutical compositions will include at least one of apharmaceutically acceptable vehicle, carrier, diluent, or excipient, inaddition to one or more neurotrophin and inhibitor of neurotrophindegradation and, optionally, other components. Pharmaceuticallyacceptable excipients for therapeutic use are well known in thepharmaceutical art, and are described herein and for example, inRemington's Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro,ed., 18. sup.th Edition, 1990) and in CRC Handbook of Food, Drug, andCosmetic Excipeints, CRC Press LLC (S. C. Smolinski, ed., 1992). Thepharmaceutical compositions of the present invention are formulated toallow the compounds contained therein to be bioavailable uponadministration of the composition to a subject. The level ofneurotrophin at the site of treatment or in circulation afteradministration can be monitored by various well-established techniques,such as chromatographic or antibody based (e.g., ELISA) assays. See e.g.Hochhaus et al., BMC Pediatrics 1:2, 2001 and Cai et al., J Neurosci.,21(13): 4731-4739 (2001).

Other optional pharmaceutically acceptable excipients are those thatmay, for example, aid in the administration of the formulation (e.g.,anti-irritant, polymer carrier, adjuvant) or aid in protecting theintegrity of the components of the formulation (e.g., anti-oxidants andpreservatives). The compositions the instant disclosure may be providedin various forms, depending on the amount and number of differentpharmaceutically acceptable excipients present. For example, theneurotrophic composition may be in the form of a solid, a semi-solid, aliquid, a lotion, a cream, an ointment, a cement, a paste, a gel, or anaerosol. In certain embodiments, the compositions are in the form of aliquid or gel. The pharmaceutically acceptable excipients suitable foruse in the neurotrophic compositions as described herein may include,for example, a viscosity-increasing agent, a buffering agent, a solvent,a humectant, a preservative, a chelating agent, an emollient, anantioxidant, an adjuvant, and the like.

In certain embodiments, compositions of neurotrophins and/orneurotrophin inhibitors in combination with a carrier, diluent, orexcipient may also include agent for improving solubility, absorption,stability and other properties, as are known in the art. The releasedsubstance or substances may include any agent capable of modulating theactivity of the neurotrophin within the region, and may includequantities of neurotrophin, inhibitor of degradation of the neurotrophinor both. The released substance or composition may include precursors orcomponents of neurotrophins which upon delivery into a neural tissue areprocessed to produce a neurotrophin such than an increase in theconcentration of the substance in the tissue produces a correspondingincrease in activity of the neurotrophin. For example, an increase inneurotrophin activity may be due to an increase in neurotrophinconcentration. The released compositions may include more than onesubstance that has neurotrophic effects, or may include more than onesubstance that acts as an inhibitor of degradation of neurotrophin, ormay include one or more neural support substances, and any combinationthereof.

In some embodiments, the neurotrophin may be a cellular second messenger(also referred to simply as a second messenger), which may be releasedalone or in combination with the release of another neurotrophin and/oran inhibitor of degradation of the second messenger. As used herein, a“cellular second messenger” may be any chemical, biological agent orcompound that mediates cellular activity within the cells of the sensoryorgan by relaying intracellular signals from an extracellular moleculebound to the cell surface and which creates a resulting neurotrophiceffect. The cellular second messenger may be cyclic AMP ( cAMP oradenosine 3′,5′-cyclic monophosphate) or one of its biochemical orfunctional analogs which results in biochemical reactions within a cellsimilar to those triggered by cAMP. In some cases, a second messengerfunctional analog may be a substance which is part of the same normalintracellular signaling cascade chain as the second messenger. As willbe understood by one skilled in the art, the functional concentration ofthe second messenger is based on the concentration of the secondmessenger as well as the concentration of any analogs combined, relativeto their respective concentrations and activity kinetics. However, incertain embodiments a second messenger may be released extracellularlyto produce an increase in extracellular concentration of the secondmessenger, following which active or passive transport of the secondmessenger across the cell membrane may result in an increase in thesecond messenger concentration within a cell.

As diagrammed in FIGS. 2, 3 and 4, a release device such as 60, 70 maybe controlled by a control signal from controller 80. The nature of thecontrol signal will depend upon the particular release device used, andthe generation of suitable control signals is known in the relevant art.In some embodiments, a voltage or current control signal may be used. Insome embodiments a voltage or current generated by the controller may beused to generate a magnetic field or provide heating in the situationthat direct control of the release device is based on magnetic field orheating. These are merely examples and other control mechanisms may besuitable for other types of release devices. In some embodiments, therelease device may generate a status signal that can be received by thecontroller. Connection of one or more release devices to the controllerfor transmission of control and status signals can be via various meansknown in the art, including by electronic wiring or cabling, or by awireless connection such as through radio frequency signals. The releasedevice may also include one or more transmitters or receivers as neededto receive control signals and transmit status signals.

The choice of implant site for the release device or devices will dependon the intended neurotrophin target cell(s) or tissue and the particularembodiment. In some cases, a release device (or a portion thereof) maybe implanted within a sensory organ (e.g., within the posterior chamberof the eye for access to the retina), or within the scala tympani orscala vestibuli of the cochlea, for access to hair cells. In some cases,a release device will be implanted within or adjacent to the brain orcentral nervous system. In some cases, the implant location may be nearthe tissue of interest, such as the olfactory bulbs or the spinalcolumn. In some cases, the release device may include a thin tube or thelike that can be threaded into a small space for targeted delivery of acomposition, while the remainder of the release device (which mightinclude, for example, a reservoir of the composition) could be implantedin an adjacent region with more available space. The neurotrophin and/orthe inhibitor of the degradation of the neurotrophin and/or the neuralsupport substance may be delivered into the interior or to the exteriorof a sensory organ, including delivery into a cell or a blood vesselinternal to or connected to the sensory organ. In some embodiments,multiple release devices may be used. These may include differentrelease devices for releasing different substances, as illustrated inFIG. 2, or multiple release devices for releasing a single substance.Release devices may be implanted in several different locations in or inthe vicinity of the neural tissue or structure that is the target of thetreatment.

In some embodiments, the concentration of neurotrophin is monitored andlevels are regulated over time through the addition of additionalneurotrophin, the addition of inhibitor of degradation of theneurotrophin and/or the addition of neural support substance. In someembodiments, the concentration of neurotrophin may be detected through asensor or sensor device and the sensor data coupled to the controller.Implantable sensors have been developed for in vivo detection of variousanalytes, including glucose, proteins, enzymes, metabolites, and toxins.Such sensors frequently are made up of a chemically selective component,which is often biological in nature, in combination with a transducingdevice. Examples of selective chemical processes include selectiveabsorption into a polymer, selective absorption or binding to a membraneor coated surface (which may take advantage of specificity ofantibodies, enzymes, single strands of DNA, for example), or selectivepermeability through a biological or bio-based membrane. The selectiveprocess of the sensor is typically associated with a change in aproperty, for example, an optical, mechanical, electrical, or chemicalproperty, that can be detected by the transducing device, which is oftena microfabricated MEMS-type device. Examples of sensors suitable for usein various embodiments include those disclosed in U.S. Pat. Nos.6,201,980, 6,278,379 6,480,730, 6,673,596, 6,750,311, 6,751,491,6,754,536, 6,770,179, and RE38525, and U.S. Published PatentApplications Nos. 20030032892, 20030158584, 20030224735, and20040140209, all of which are incorporated herein by reference in theirentirety. The invention is not limited to any particular type ofsensors, and the above are merely exemplary. The appropriate choice ofsensor will depend on the analyte of interest, intended implantationsite, duration of treatment, and other variables which will beidentifiable by those of skill in the art.

The sensor or sensors may be of any type or types capable of detectingthe concentration of a neurotrophin and/or the inhibitor of degradationin a therapeutically relevant region. Concentrations may be detecteddirectly or indirectly through the detection of biological activityrelated to the concentration of the substance(s) of interest. The regionmay be a sensory organ, including those that are auditory, olfactory,visual or somatosensory. The region may be within the peripheral orcentral nervous system. The choice of sensor(s) used will depend on thespecific embodiment, particularly the substance(s) to be detected, thelocations and the expected length of time over which the sensor will beneeded. In general, sensors that are suitable for continuous use (overat least some generally defined period, e.g. a few days, weeks, ormonths) are preferred over sensors suitable for one-time use althoughthe selection of one or more sensors will depend on the particularembodiment. In some embodiments, no sensor will be used and the releasewill occur once or based on a preset delivery schedule. Such embodimentsmay include those that test patient response. Sensors of different typesmay be combined in a particular embodiment. Sensors may generate asignal that is a function of the concentration of the detectedsubstance. The signal may be an electrical signal. Certain sensors maygenerate an electrical signal (current or voltage) directly, whileothers may generate another type of signal (optical, thermal pressure,etc.) which may be converted to an electrical signal by suitabletransduction means, as are known in the art. Various types of signalgenerated by the sensor and means by which the signal is transmitted tothe controller will be appropriate for different embodiments.

As will be appreciated by one skilled in the art, any detectedconcentration of the neurotrophin and/or the inhibitor of degradation,as reported by the sensor(s) is inherently an estimate based on theactual concentration of the detected substance at any given time.Moreover, the sensor may be configured to measure concentration of thedetected substance at a location that is temporally and/or spatiallynear, rather than at, the location of interest or the target location.Therefore, while it is presumed that a relationship exists between themeasured concentration and the concentration at the target location fordelivery, it is not required that the measured concentration beidentical to the concentration at the target location for delivery. Insome embodiments, multiple sensors may be used. These may includedifferent sensors for detecting different substances, as illustrated inFIG. 2, or multiple sensors for detecting a single substance. In someembodiments and as depicted in FIG. 2, there may be one or more sensorsto detect the concentration of neurotrophin as well as one or moresensors to detect the concentration of inhibitor of degradation of theneurotrophin. Sensors may be implanted in several different locationswithin or in the vicinity of the neural tissue or structure that is thetarget location for delivery. As with the release devices, sensors maybe connected to the controller for transmission of data and possiblycontrol signals via various connection methods known in the art. Theconnections are not limited to any particular connection method and maybe made by electronic or optical wiring or cables, or by a wirelessconnection such as by radio frequency signals. The sensors may includeone or more transmitters or receivers as needed to transmit data signalsand in some embodiments, receive control signals.

Controllers used in various embodiments, as exemplified herein (e.g.controller 80 in FIGS. 2, 3 and 4), may be configured in various waysdepending on the embodiment. The controller may be configured to receivesignals from sensors and/or release devices, and to send control signalsto release devices and/or sensors. The controller may be connected tosensors and release devices by various means known in the art, asdescribed above, and may include one or more transmitters or receiversfor transmitting or receiving data, status and control signals asdescribed above. The controller may be placed in various locations. Thecontroller may be external to the body of the mammal, including beinglocated at a distance from the body or capable of being worn on or nearthe surface of the body. The controller may in addition be connected toremote devices by any connection means known in the art.

One or more parameters may be controlled by the controller. As depictedin FIG. 2, the controller may receive information from one or moresensors (e.g. sensors 50 and 90) regarding concentrations ofneurotrophin and/or inhibitor of neurotrophin degradation. In additionthe controller may receive information regarding the concentration ofone or more neural support substances. The controller may also receiveinformation from one or more sensors regarding one or more biologicalactivities arising from a particular level of neurotrophin and/orinhibitor of degradation of neurotrophin and/or neural supportsubstance. The controller may generate one or more signals that lead tothe release of substances from one or more release devices (e.g. releasedevices 60 and 70). As noted above, the two sensors and two releasedevices depicted in FIG. 2 are merely exemplary, and the system mayinclude larger or smaller numbers of sensors and release devices. Inmany cases, the desired end result is to modulate the concentration ofneurotrophin within the tissue or cellular structure of interest;however, in many embodiments this may be achieved by elevating one orboth of the concentration of neurotrophin and concentration of inhibitorof neurotrophin degradation either within or nearby the tissue orcellular structure of interest.

Other embodiments of the method include regulating the concentration ofthe neurotrophin and/or the inhibitor of degradation over time andmonitoring the levels of the concentration of neurotrophin over time.The concentrations may be kept constant over time, vary in apredetermined manner, be adjusted to keep the concentration within someset parameters and/or be regulated based on the concentration ofneurotrophin detected by the sensor.

In some embodiments, the method includes modulating the level of aneurotrophin in a sensory organ of a subject and includes detecting thelevel of the neurotrophin in the sensory organ, comparing the detectedlevel with a target level of neurotrophin, and if the detected level isless than the target level, releasing an amount of at least one of theneurotrophin and an inhibitor of degradation of the neurotrophin. Thetarget level may be defined as a range of concentrations of theneurotrophin and may vary over time. The target level may be cyclic. Thetarget level of neurotrophin may be based on the concentration ofneurotrophin within the sensory organ, in the vicinity of the sensoryorgan or within a cell of the sensory organ. The rate of release may becontrolled based on current and/or target values to provide a gradualramping up of the release rate and may be controlled by any of thevarious control methods that are known or may be devised by those ofskill in the art such as proportional-integral-derivative (PID) control.

The concentration of neurotrophins(s) in a tissue or cell of interestare modulated by elevating the amounts of neurotrophin and/or inhibitorof neurotrophin degradation and/or neural support substance releasedinto or in the vicinity of the tissue, sensory or neural structure, orcell of interest. In many situations, it may be possible to modulate thelevel of neurotrophin in several ways such as elevating theconcentration of neurotrophin, elevating the concentration of inhibitorof degradation or elevating the concentration of neural supportsubstance or some combination of these in order to achieve the desiredtarget level of neurotrophin. In some situations, it may be desirable torelease multiple neurotrophins, multiple inhibitors of degradation ofneurotrophin or both. In some cases, the level(s) may be elevated to“biologically effective” levels, which are levels necessary for theintended biological effect on the neuron(s) of interest. For example,the biologically effective level of neurotrophin within a diseased organmay be equivalent to that of a comparable but non-diseased organ, or itmay be to a higher level as needed to stimulate neurotrophic effects. Insome situations the level(s) may be elevated one or a few fold while inothers the biologically effective level(s) may be several fold higherthan before elevation. In some cases the level(s) may be elevated to“therapeutically effective” levels which are levels necessary to achievea desired therapeutic effect. For example in a situation where thetherapeutic effect desired or intended is regeneration of a neuron, thetherapeutically effective levels are those in a range that may beexpected to stimulate regeneration. In some cases, the level(s) may beincreased to “normal” levels, which are levels in the range of thosefound or predicted to be found in the same anatomic location in healthyindividuals. In some cases, the level(s) are increased from one or more“baseline” levels, which are levels detected prior to start of treatmentor detected during a time interval between compound release(s).Depending on the intended effect, the levels may be increased to ortoward normal levels (in cases where the initial level was below normal)or increased to higher-than normal levels. The target level may be apredetermined constant value (which might be, for example, a value thatrepresents a desirable normal or supra-normal value). The target levelmay be calculated as a percentage or multiple of the initialconcentration value. The target level may have a marked time-dependenceand be cyclic, including having multiple target levels over multipletime points. In some embodiments, a time-dependent series of targetvalues may be stored or calculated. Such values may be predeterminedvalues stored in one or more memory devices. For example, in certainembodiments the target level may initially be a higher than normalvalue, in order to promote repair or recovery following a period ofsub-normal concentrations, and then after a period of time, the targetvalue may be lowered to a normal level. Various schemes may be devisedfor determining a target value as a function of the current and aneventual target value.

As an example, in some embodiments, the controller may adjust the amountof the substance(s) of interest (e.g., neurotrophin, inhibitor ofneurotrophin degradation, or neural support substance) delivered by thesystem such that the concentration of the neurotrophin, theconcentration of the inhibitor of degradation, on both may be increasedby up to about 50% over preexisting levels. In other embodiments, theconcentration of the substance(s) of interest may be increased by abouttwo-fold over the preexisting levels. In still other embodiments, theconcentration of the substance(s) of interest may be elevated to abiologically or therapeutically effective level. The concentration ofthe substance(s) of interest may also be increased to level(s) that aredetectable by the sensors or other means.

In some embodiments, some of the neurotrophin and/or the inhibitor ofdegradation of the neurotrophin and/or the neural support substance maybe produced by the mammal itself while in others the neurotrophin and/orthe inhibitor of degradation of the neurotrophin and/or the neuralsupport substance may be entirely supplied by the method, and modelsthat take into account the influence of endogenous and exogenous sourcesmay be included in the control scheme. In some embodiments, theneurotrophin and/or the inhibitor of degradation of the neurotrophin areintroduced as precursors and endogenous factors alter the precursor(s)to metabolically active forms after release. The methods and systemsdescribed herein, therefore, include precursors, metabolites and otherfunctionally equivalent substances to the neurotrophins, inhibitors ofdegradation of neurotrophin and neural support substances described.

Electrical circuitry, such as processor 120 (presented in the controller100 of FIG. 3) may control the release of neurotrophin, inhibitor ofdegradation, neural support substance or some combination of these inorder to modulate the concentration of neurotrophin toward a targetlevel. The concentration of neurotrophin is determined based on signalsfrom detectors 50 and 90 in the embodiment diagrammed in FIG. 2, forexample. Based on current levels of neurotrophin and inhibitor, theprocessor produces a control signal to drive the release devices(s) torelease the composition(s) in order to modulate the levels to targetlevels in the exemplary embodiment shown in FIG. 2. The rate of releaseof the composition may occur over a predetermined time period to providea controlled rate of release of the composition. The targetconcentration of the composition may be constant over time, it may varyas a function of time over a predetermined time period, it may comprisea predetermined sequence of target values, it may be calculated as afunction of the detected concentration, or a different time periods thetarget concentration may be determined by any of the aforementionedcalculations.

The processor 120 or another portion of the system may include a memorydevice capable of storing a target set of levels of neurotrophin orother parameters such as, for example, times and amounts of substance(s)to be released. In some embodiments, the method includes detecting theconcentration of the neurotrophin in a therapeutically relevant regionof the nervous system of a subject, calculating a quantity of acomposition to be released in the region and releasing the calculatedquantity in the region. The detection and/or release may happen at oneor more times in one or more locations. The calculated quantity may beany quantity of the composition that is sufficient to adjust thedetected concentration of neurotrophin toward a target concentration.The detection and release may be repeated over time in order to obtainand maintain a desired concentration of neurotrophin in the region.

The processor 120 may be of a number of types that are capable ofcomparing a directly or indirectly detected concentration of theneurotrophin with a target level in order to compute a quantity of acomposition to be released to adjust the detected concentration toward atarget concentration. Various combinations of hardware, firmware,software, analog and/or digital circuitry may be used in the controller.The controller may be implanted at or near the site of the sensors orrelease devices, or it may be located at a distance from these devicesand connected via a wireless link, as described above. In someembodiments, the processor is worn externally relative to the skinsurface of the subject. The control signal generator may be of any typethat is capable of generating a control signal representing a computedquantity of the composition to be released. The computed quantity of thecomposition may be intended to be released over a fixed time period sothat the controlled release device controls a rate of release of thecomposition.

In some aspects, the system that modulates the concentration of aneurotrophin may include a sensor, a feedback signal generator, atransmitter, a receiver and/or a controlled release device such as thesensors 50, 90 of FIG. 2. In some embodiments, the sensor is capable ofdetecting the concentration of the neurotrophin in the vicinity of ahighly innervated tissue of a mammal. The feedback signal generator maybe capable of representing the detected concentration of neurotrophin ina feedback signal. The transmitter may be adapted for transmitting thefeedback signal to a remote processor. In some embodiments, the receiveris adapted for receiving a control signal from said remote processor.The controlled release device may be implanted in the vicinity of ahighly innervated tissue and controllable by the control signal torelease a composition capable of modulating the concentration of theneurotrophin in the vicinity of the highly innervated tissue.

Those having skill in the art will recognize that the state of the arthas progressed to the point where there is little distinction leftbetween hardware and software implementations of aspects of systems: theuse of hardware or software is generally (but not always, in that incertain contexts the choice between hardware and software can becomesignificant) a design choice representing cost vs. efficiency tradeoffs.Those having skill in the art will appreciate that there are variousvehicles by which processes and/or systems described herein can beeffected (e.g., hardware, software, and/or firmware), and that thepreferred vehicle will vary with the context in which the processes aredeployed. For example, if an implementer determines that sped andaccuracy are paramount, the implementer may opt for a hardware and/orfirmware vehicle, alternatively, if flexibility is paramount, theimplementer may opt for a solely software implementation, or, yet againalternatively, the implementer may opt for some combination of hardware,software, and/or firmware. Hence, there are several possible vehicles bywhich the processes described herein may be effected, none of which isinherently superior to the other in that any vehicle to be utilized is achoice dependent upon the context in which the vehicle will be deployedand the specific concerns (e.g., speed, flexibility, or predictability)of the implementer, any of which may vary. Those skilled in the art willrecognize that optical or biological aspects of implementations willrequire optically-oriented or biologically-oriented hardware, software,and or firmware.

One exemplary application for the methods and systems described hereinis to restore the sensory hair cells within the cochlea which lead tohearing loss when damaged. A common cause of acquired hearing loss isdamage to the sensory hair cells within the cochlea, which can arise dueto excessive exposure to loud noise, infection and/or ototoxic drugs.See Wang et al., J Neurosci., 23(24):8596-8607 (2003). Under normalmetabolic conditions, damage to hair cells limits their function andtherefore the ability of the individual to hear is reduced. See Kawamotoet al., J Neurosci., 23(11); 4395-4400, 2003. An implantable releasedevice or devices as described herein could be implanted within thecochlea or in a therapeutically effective region to the cochlea in aperson or animal that has hair cell damage. The release device(s) couldthen be used to increase the metabolic levels of neurotrophin in theregion of the hair cells, initiating and promoting the growth ofreplacement hair cells and/or repairing and maintaining those that existas described herein. For background, see the 36^(th) KarolinskaInstitutet Nobel Conference: To Restore Hearing, 9-13 June 2002,Krusenberg, Sweden. In certain embodiments, the neurotrophin modulatingsubstance(s) or compositions described herein could be released inconjunction with ototoxid drugs to prevent hearing loss as a negativesides effect of the drug therapy. In other embodiments, the substance(s)or compositions described herein could be released to repair previousdamage. For example, the release could include ongoing release, releaseat periodic intervals, or only one or a limited umber of releases toretain and repair hearing.

The foregoing detailed description has set forth various embodiments ofthe devices and/or processes via the use of block diagrams, flow charts,and/or examples. Insofar as such block diagrams, flowcharts, and/orexamples contain one or more functions and/or operations, it will beunderstood by those within the art that each function and/or operatorwithin such block diagrams, flowcharts or examples can be implemented,individually and/or collectively, by a wide range of hardware, software,firmware, or virtually any combination thereof. In one embodiment,several portions of the subject matter subject matter described hereinmay be implemented via Application Specific Integrated Circuits (ASICs),Field Programmable Gate Arrays (FPGAs), digital signal processors(DSPs), or other integrated formats. However, those skilled in the artwill recognize that some aspects of the embodiments disclosed herein, inwhole or in part, can be equivalently implemented in standard integratedcircuits, as one or more computer programs running on one or morecomputers (e.g., as one or more programs running on one or more computersystems), as one or more programs running on one or more processors(e.g., as one or more programs running on one or more microprocessors),as firmware, or as virtually any combination thereof, and that designingthe circuitry and/or writing the code for the software and/or firmwarewould be well within the skill of one of skill in the art in light ofthis disclosure. In addition, those skilled in the art will appreciatethat some of the mechanisms of the subject matter described herein arecapable of being distributed as a program product in a variety of forms,and that an illustrative embodiment of the subject matter describedherein applies equally regardless of the particular type ofsignal-bearing media used to actually carry out the distribution.Examples of signal-bearing media such as may be used to store programsand data include, but are not limited to, the following: recordable typemedia such as floppy disks, hard disk drives, CD ROMs, digital tape, andcomputer memory; and transmission type media such as digital and analogcommunication links using TDM or IP based communication links (e.g.,packet links).

In a general sense, those skilled in the art will recognize that thevarious aspects described herein which can be implemented, individuallyand/or collectively, by a wide range of hardware, software, firmware orany combination thereof can be viewed as being composed of various typesof “electrical circuitry.” Consequently, as used herein “electricalcircuitry” includes, but is not limited to electrical circuitry havingat least one discrete electrical circuit, electrical circuitry having atleast one integrated circuit, electrical circuitry having at least oneapplication specific integrated circuit, electrical circuitry forming ageneral purpose computing device configured by a computer program (e.g.,a general purpose computer configured by a computer program which atleast partially carries out processes and/or devices described herein,or a microprocessor configured by a computer program which at leastpartially carries out processes and/or devices described herein),electrical circuitry forming a memory device (e.g., forms of randomaccess memory), and/or electrical circuitry forming a communicationsdevice (e.g., a modem, communications switch, or optical-electricalequipment). The foregoing described aspects depict different componentscontained within, or connected with, different other components. It isto be understood that such depicted architectures are merely exemplary,and that in fact many other architectures can be implemented whichachieve the same functionality. In a conceptual sense, any arrangementof components to achieve the same functionality is effectively“associated” such that the desired functionality is achieved. Hence, anytwo components herein combined to achieve a particular functionality canbe seen as “associated with” each other such that the desiredfunctionality is achieved, irrespective of architectures or intermedialcomponents. Likewise, any two components so associated can also beviewed as being “operably connected”, or “operably coupled”, to eachother to achieve the desired functionality

While particular aspects of the present subject matter described hereinhave been shown and described, it will be obvious to those skilled inthe art that, based upon the teachings herein, changes and modificationsmay be made without departing from this subject matter described hereinand its broader aspects and, therefore, the appended claims are toencompass within their scope all such changes and modifications as arewithin the true spirit and scope of this subject matter describedherein. Furthermore, it is to be understood that the invention isdefined by the appended claims. It will be understood by those withinthe art that, in general, terms used herein, and especially in theappended claims (e.g., bodies of the appended claims) are generallyintended as “open” terms (e.g., the term “including” should beinterpreted as “including but not limited to,” the term “having” shouldbe interpreted as “having at least,” the term “includes” should beinterpreted as “includes but is not limited to,” etc.). It will befurther understood by those within the art that if a specific number ofan introduced claim recitation is intended, such as intent will beexplicitly recited in the claim, and in the absence of such recitationno such intent is present. For example, as an aid to understanding, thefollowing appended claims may contain usage of the introductory phrases“at least one” and “one or more” to introduce claim recitations.However, the use of such phrases should NOT be construed to imply thatthe introduction of a claim recitation by the indefinite articles “a” or“an” limits any particular claim containing such introduced claimrecitation to inventions containing only one such recitation, even whenthe same claim includes the introductory phrases “one or more” or “atleast one” and indefinite articles such as “a” or “an” (e.g., “a” and/or“an” should typically be interpreted to mean “at least one” and/or “oneor more”), the same holds true for the sue of definite articles used tointroduce claim recitations. In addition, even if a specific number ofan introduced claim recitation is explicitly recited, those skilled inthe art will recognize that such recitation should typically beinterpreted to mean at least the recited number (e.g., the barerecitation of “two recitations,” without other modifiers, typicallymeans at least two recitations, or two or more recitations).Furthermore, in those instances where a convention analogous to “atleast one of A, B, and C, etc.” is used, in general such a constructionis intended in the sense of one having skill in the art would understandthe convention (e.g., “a system having at least one of A, B, and C”would include but not be limited to systems that have A alone B alone, Calong, A and B together. A and C together. B and C together, and/or A,B, and C together). In those instances where a convention analogus to“at least one of A, B, or C, etc.” is used, in general such aconstruction is intended in the sense of one having skill in the artwould understand the convention (e.g., “a system having at least one ofA, B, or C” would include but not be limited to systems that have Aalone, B alone, C alone, A and B together, A and C together, B and Ctogether, and/or A, B, and C together).

As used herein, the term “about” or “consists essentially of” refers to±15% of any indicated structure, value, or range. Any numerical rangesrecited herein (e.g., concentrations, ratios, percentages, sequences,etc.) are to be understood to include any integer within that range and,where applicable, fractions thereof, such as one tenth and one hundredthof an integer (unless otherwise indicated).

The above referenced technical articles are specifically incorporatedherein by reference in their entirety for all that they disclose andteach. In an event of any conflict between the instant application and areferenced technical article, the instant application controls.

Although the methods, devices, systems and approaches herein have beendescribed with reference to certain preferred embodiments, variousmodifications may be made without deviating from the spirit and scope ofthe invention. As illustrated by the foregoing examples, various choicesof sensor and release device configuration may be within the scope ofthe invention. As has been discussed, the choice of system configurationmay depend on the intended applications of the system, the environmentin which the system is used, cost, personal preference or other factors,signal analysis and release device control processes may be modified totake into account choices of sensor, release device, and implant site,released and detected substances, and system configuration, and suchmodifications, as known to those of skill in the relevant arts, may fallwithin the space of the invention. Therefore, the full spirit or scopeof the invention is defined by the appended claims and their legalequivalent and is not be limited to the specific embodiments describedherein.

1. A method comprising: elevating, with an implanted neurotrophin release device, the level of a neurotrophin within a sensory organ of a mammal; elevating, with an implanted inhibitor release device, the level of at least one inhibitor of degradation of said neurotrophin within said sensory organ; and controlling the levels of said neurotrophin over time, wherein controlling includes: monitoring, with at least one implanted sensor device, the level of the neurotrophin within the sensory organ to determine whether at least one desired neurotrophin concentration target level of the neurotrophin is present; and adding, with the implanted neurotrophin release device, additional neurotrophin in a quantity sufficient to adjust the neurotrophin concentration toward the at least one desired neurotrophin concentration target level.
 2. The method as in claim 1, further comprising: monitoring the level of said neurotrophin within the sensory organ.
 3. The method as in claim 1, further comprising: elevating, with an implanted neurotrophin release device, the level of neurotrophin to a predetermined level.
 4. The method as in claim 1, further comprising: determining a target level of neurotrophin in the sensory organ and elevating, with an implanted neurotrophin release device, the level of neurotrophin to the target level.
 5. The method as in claim 1, further comprising: controlling the levels of said at least one inhibitor of the degradation of said neurotrophin over time.
 6. The method of claim 5, wherein the control of the level of said at least one inhibitor of the degradation of said neurotrophin is a function of the level of said neurotrophin over time.
 7. The method as in claim 1, wherein the mammal is a human.
 8. The method as in claim 1, wherein the sensory organ is auditory, olfactory, visual, or somatosensory.
 9. The method as in claim 1, wherein the sensory organ is the cochlea, the olfactory bulb or the retina.
 10. The method as in claim 1, further comprising; releasing a neural support substance.
 11. The method of claim 1, wherein the implanted neurotrophin release device comprises: a reservoir; and a controllable pump mechanism.
 12. The method of claim 1, wherein the implanted neurotrophin release device comprises: a MEMS-type drug delivery device.
 13. The method of claim 1, wherein the implanted neurotrophin release device and the implanted inhibitor release device are an integrated unit.
 14. The method of claim 1, wherein the implanted neurotrophin release device, is configured for control by proportional-integral-derivative (PID) control.
 15. The method of claim 1, wherein the at least one implanted sensor device includes a chemically selective component and a transducing device. 